Explore the vast range of titles available.

During nocturnal sleep, blood pressure (BP) \"dips\" compared to diurnal BP, reducing stress on the cardiovascular system. Both the hypotensive response elicited by acute aerobic exercise and sleep quality can impact this dipping response. The purpose of this study was to investigate the effects of aerobic exercise timing on circadian BP changes and sleep architecture. Twenty prehypertensive subjects completed the study. During four test sessions, participants first completed a graded exercise test to exhaustion and then performed 30 minutes of treadmill exercise at 7 am (7A), 1 pm (1P), and 7 pm (7P) in a random, counterbalanced order at 65% of the heart rate obtained at peak oxygen uptake. An ambulatory cuff was used to monitor BP responses during 24 hours following exercise, and an ambulatory sleep-monitoring headband was worn during sleep following each session. Aerobic exercise at 7A invoked a greater dip in nocturnal systolic BP than exercise at 1P or 7P, although the greatest dip in nocturnal diastolic BP occurred following 7P. Compared to 1P, 7A also invoked greater time spent in deep sleep. These data indicate that early morning may be the most beneficial time to engage in aerobic exercise to enhance nocturnal BP changes and quality of sleep.

BackgroundNUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1. BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called “megadomains” with the overexpression of corresponding oncogenes, including MYC. We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable.MethodsWe integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single-labeled and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient-derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of NUTM1 fusions (N=165). We created an αPRAME425 T-cell receptor (TCR) × SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME425 TCR bispecific T-cell engager, as well as αPRAME425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro.ResultsWe identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions (BRD4::NUTM1, BRD3::NUTM1, and NSD3::NUTM1). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived human leukocyte antigen (HLA) ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME425) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME312) or HLA-A*02:01/YLHARLREL (PRAME462). The αPRAME425 TCR × SP34 αCD3 bispecific molecule and αPRAME425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME+ NUT carcinoma cells.Conclusions PRAME is highly and frequently expressed in NUT carcinoma, and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.

BackgroundCurrent immune checkpoint inhibitor immunotherapy relies on the presence of a pool of pre-existing neoantigen-specific T cells that can be unsuppressed and leveraged to eliminate cancer cells. However, in many patients in many cancers, the pre-existing T cell repertoire is unable to eliminate the tumor even after immune checkpoint therapy, suggesting that a targeted neoantigen vaccination approach could improve response to immune checkpoint inhibitor therapy. Murine antigen models exist to investigate neoantigen vaccine approaches, but most current murine neoantigen models rely on OVA or viral antigens that might have very different immunogenic properties to human neoantigens. Here, we investigate the landscape of predicted neoantigens in BBN963, a syngeneic murine bladder cancer model with endogenous neoantigens generated through mouse exposure to the tobacco carcinogen BBN in their drinking water (figure 1).MethodsWe used LENS to predict neoantigens in the BBN963 cell line. We performed RNAseq on the BBN963 cell line treated for 72 hours with DMSO (control) or entinostat, an HDAC inhibitor that upregulates expression of some predicted BBN963 neoantigens. We performed DNAseq on BBN963 tumors after 4 weeks of treating the mice with normal or entinostat chow to assess for immunoediting at the DNA level.1 From the list of LENS-predicted BBN963 neoantigens we assessed features of antigens with of strong immunogenic potential (strong binding affinity, low agretopicity, high binding stability, low baseline expression level), upregulated with entinostat in vitro, and immunoedited with entinostat treatment in vivo.ResultsFrom LENS, we predicted 422 antigens from a variety of genomic sources (SNV, self-antigen, fusion event, virus, and indel). 147 of these antigens were immunoedited in vivo. A high degree of overlap existed between the neoantigens predicted by LENS from three biological replicate tumors (figure 2). Furthermore, different neoantigens are expressed by BBN963 cells in culture depending on concentration of entinostat.ConclusionsWe present an endogenous neoantigen murine cancer model containing over 400 predicted neoantigens from multiple genomic sources. Some of these neoantigens have strong immunogenicity features. The BBN963 model will be invaluable in future investigation of tumor-immune evolution, immunoediting, neoantigen-specific CD8 T cell responses, and neoantigen vaccination (figure 3).ReferenceAndrew S Truong, Mi Zhou, Bhavani Krishnan, Takanobu Utsumi, Ujjawal Manocha, Kyle G Stewart, Wolfgang Beck, Tracy L Rose, Matthew I Milowsky, Xiaping He, Christof C Smith, Lisa M Bixby, Charles M Perou, Sara E Wobker, Sean T Bailey, Benjamin G Vincent, William Y Kim. Entinostat induces antitumor immune responses through immune editing of tumor neoantigens. J. Clin. Invest. 2021;131.Abstract 848 Figure 1Generation of BBN963 endogenous neoantigen murine cancer model. A C57BL/6J mice were treated with BBN orally in drinking water for 4–6 months. The tumor from one female mouse was harvested and used to generate the immortalized BBN963 cancer cell line. To establish subcutaneous tumors, BBN963 is cultured for one week in vitro and then implanted with matrigel by flank injection. After 4 weeks of growth in the recipient mouse, the mouse and tumor are ready for treatment by entinostat, anti-PD-1, and/or neoantigen vaccinationAbstract 848 Figure 2LENS prediction of BBN963 neoantigens. We assessed overlap in the neoantigens predicted by LENS from three separate BBN963 tumors (A). From in vitro culture with DMSO, 1.5 uM entinostat, and 3uM entinostat, we assessed overlap in the neoantigens present in each treatment group (B). Neoantigens from multiple genomic sources were predicted from the in vitro culture BBN963 cells (C)Abstract 848 Figure 3Immunogenicity potential of LENS-predicted BBN963 neoantigens. LENS-predicted SNV neoantigens from cell culture RNAseq and DNAseq were filtered based on immunoediting in vivo and characterized based on immunogenicity features (A). Among the 147 immunoedited SNV neoantigens, we assessed binding stability and binding affinity (B), agretopicity from LENS, and gene expression in untreated mouse tumors (C). We assessed the features of the neoantigens with strong binding affinity, high binding stability, low agretopicity, and low baseline gene expression (D-E)

Exercise has substantial health benefits, but the effects of exercise on immune status and susceptibility to respiratory infections are less clear. Furthermore, there is limited research examining the effects of prolonged exercise on local respiratory immunity and antiviral activity. To assess the upper respiratory tract in response to exercise, we collected nasal lavage fluid (NALF) from human subjects (1) at rest, (2) after 45 min of moderate‐intensity exercise, and (3) after 180 min of moderate‐intensity exercise. To assess immune responses of the lower respiratory tract, we utilized a murine model to examine the effect of exercise duration on bronchoalveolar lavage (BAL) fluid immune cell content and lung gene expression. NALF cell counts did not change after 45 min of exercise, whereas 180 min significantly increased total cells and leukocytes in NALF. Importantly, fold change in NALF leukocytes correlated with the post‐exercise fatigue rating in the 180‐min exercise condition. The acellular portion of NALF contained strong antiviral activity against Influenza A in both resting and exercise paradigms. In mice undergoing moderate‐intensity exercise, BAL total cells and neutrophils decreased in response to 45 or 90 min of exercise. In lung lobes, increased expression of heat shock proteins suggested that cellular stress occurred in response to exercise. However, a broad upregulation of inflammatory genes was not observed, even at 180 min of exercise. This work demonstrates that exercise duration differentially alters the cellularity of respiratory tract fluids, antiviral activity, and gene expression. These changes in local mucosal immunity may influence resistance to respiratory viruses, including influenza or possibly other pathogens in which nasal mucosa plays a protective role, such as rhinovirus or SARS‐CoV‐2. Exercise duration differentially alters the cellularity of respiratory tract fluids, antiviral activity, and lung gene expression. The change in nasal fluid leukocytes correlated with the post‐exercise fatigue rating after 180 min of exercise. These changes in local mucosal immunity may influence resistance to respiratory viruses, including influenza or possibly other pathogens in which nasal mucosa plays a protective role, such as rhinovirus or SARS‐CoV‐2.

Immune checkpoint inhibition (ICI) is clinically active against multiple cancers, including urothelial cancer at the non-muscle invasive, muscle-invasive, and metastatic stages. Despite this, large numbers of patients experience disease progression and relapse after treatment with ICI-containing regimens. Tumor antigen-specific T cells are critical to ICI response, however few studies have evaluated the breadth and magnitude of tumor antigen-specific T cell responses with ICI therapy. In this study, we mapped the tumor antigen immunodominance hierarchy in the BBN963 model of murine basal-like bladder cancer for endogenous tumor neoantigens expressed physiologically. We used a high-throughput matrixed ELISpot assay to detect CD8 T cell responses to predicted BBN963 tumor antigens derived from multiple mutational genomic sources. We found CD8+ T cell responses were directed against a subset of tumor antigens forming a stable and reproducible immunodominance hierarchy across individual mice. Treatment with anti-PD-1 or anti-CTLA-4 did not substantially reshape this hierarchy or broadly shift dominant responses to previously defined subdominant epitopes. Predicted peptide MHC binding stability and affinity was associated with antigen immunogenicity. Cancer-testis antigens, endogenous retroviral antigens, and SNV-derived tumor antigens that were immunogenic were found across tumor subclones. By diversifying the immunogenic antigen repertoire beyond SNVs, we achieved nearly 100% tumor subclone coverage, suggesting that broader antigen selection could help immunotherapy target more tumor subclones. In conclusion, this study supports the stability of the immunodominance hierarchy under ICI therapy and a role for broadening antigen discovery to multiple expressional sources in immunotherapy design.

Safe approaches to enhance vaccine efficacy and promote desired immunological outcomes are continuously being pursued, and vaccine strategies that involve exercise or modulation of metabolic signaling pathways may offer often overlooked solutions. Acute and chronic exercise interventions have been shown to enhance both humoral and cellular immunity following vaccination, but the mechanisms behind such improvements remain to be elucidated. We evaluated the effects of exercise or metabolism-targeting agents on adaptive immunity in three separate studies. The objectives of the first study were to 1) examine the effect of acute exercise coupled with vaccination on draining lymph node dendritic cells as one mechanism through which exercise may exert immunostimulatory effects, 2) evaluate protection induced by this vaccination strategy, and 3) examine antibody responses and memory T cell populations in both sexes. Results suggest potential mechanisms through which exercise coupled with vaccination may mediate the immune response and that these effects may differ by sex. In the second study, we assessed the efficacy of incorporating metabolism-targeting pharmacological agents in a nanoparticle-based vaccine. Our findings demonstrate a potential strategy for enhancing memory T cells following vaccination against respiratory pathogens. In contrast to modulating the metabolism of immune cells through exogenous pharmacological mediators, the third study focused on identifying the extent to which aerobic exercise training alters mitochondrial characteristics and activation-induced ATP production of specific T cell subsets. Results suggest that adaptations to exercise training may extend to the mitochondria of peripheral blood naïve T cells. These findings add to the minimal body of work investigating exercise-induced metabolic alterations within adaptive immune cells. Collectively, this work contributes to the understanding of exercise- and metabolism-mediated modulation of the immune system and provides a foundation for future development of prophylactic and therapeutic interventions.

NUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing fusion oncogenes, most commonly . BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called \"megadomains\" with the overexpression of corresponding oncogenes, including . We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable. We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single- and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of fusions (N=165). We created an αPRAME T-cell receptor x SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME T-cell receptor bispecific T-cell engager, as well as αPRAME TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells . We identified as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions ( , , and ). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. expression in HEK 293T cells enhanced PRAME levels and knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived HLA ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME ) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME ) or HLA-A*02:01/YLHARLREL (PRAME ). The αPRAME T-cell receptor x SP34 αCD3 bispecific molecule and αPRAME TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against + NUT carcinoma cells. is highly and frequently expressed in NUT carcinoma and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA Class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrant clinical trials testing PRAME targeted immunotherapies in this neglected patient population. NUT carcinoma is a devastating malignancy that is recalcitrant to cytotoxic chemotherapy, T-cell checkpoint blockade, and targeted therapies in the form of bromodomain inhibitors. NUT carcinoma tumors are high in the cancer/testis gene . The oncogene most commonly causing NUT carcinoma, , contributes to these high levels. NUT carcinoma cells present PRAME epitopes on HLA Class I molecules and are susceptible to PRAME-directed, T-cell mediated cytotoxicity. Our results argue for phase I/II clinical trials testing PRAME immunotherapies like brenetafusp or anzutresgene autoleucel in + NUT carcinoma patients.

NUT carcinoma is an aggressive cancer driven by NUTM1 fusion proteins. This study evaluated antisense oligonucleotides (ASOs) targeting NUTM1 as a potential therapeutic approach. Three ASOs targeting NUTM1 and scrambled controls were tested at 10-50 nM doses in three NUT carcinoma cell lines (TC-797, 10-15, 14169) and one control line (293T). ASOs were delivered both gymnotically and using a transfection reagent. Cell viability was assessed at 48 and 72 hours using a luminescence-based assay. No ASOs showed selective inhibition of NUT carcinoma cell viability compared to controls across all conditions tested. Thus, this pilot study did not identify ASOs with activity against NUT carcinoma cells. However, it did establish preliminary protocols and generated data to inform future ASO optimization efforts targeting NUTM1 in NUT carcinoma. Further refinement of ASO design and delivery methods is needed to identify therapeutic candidates. This experiment was performed as a pilot experiment to generate data to inform future work, which should include formal hypothesis testing with a reduced number of conditions. The hypothesis of this pilot experiment was that one or more of the non-scrambled antisense oligonucleotides (ASOs) targeting NUTM1 will selectively decrease proliferation and/or viability of NUT carcinoma cells, indicated by a reduction in luminescence (as compared to treated non-NUT carcinoma and untreated NUT carcinoma control cells) using the CellTiter-Glo Luminescent Cell Viability Assay.

The studies about teenage drinking that universities are doing are not enough: People need to tell teenagers that they should know their limit. I don't believe just standing up and saying \"drinking is bad, don't drink\" will accomplish anything. If anything, it will interest teens even more.

A Registered Report is a type of research journal article in which the introduction, methods, and analysis plan are proposed and peer-reviewed prior to the execution of the study. The goal is to limit publication bias based on study findings by conducting peer review on the merits of the study before the results are known. First introduced in 2012 (Chambers, 2013; Chambers & Tzavella, 2022), this format of journal article publication has become more commonplace. Here we provide an overview of the format as well as eight core lessons we learned while preparing Registered Reports. We integrate guidelines from the literature with our experience to provide insight into the process of preparing and publishing a Registered Report for those who have not yet tried it. Though Registered Reports require researchers to invest more effort at the earlier stages of idea generation, design, and analysis planning, they will benefit from the feedback of reviewers when it is most beneficial and leave behind the fear of rejection due to unanticipated study limitations or null results. Un rapport enregistré est un type d'article de journal de recherche dans lequel l'introduction, les méthodes et le plan d'analyse sont proposés et examinés par des pairs avant l'exécution de l'étude. L'objectif est de limiter le biais de publication basé sur les résultats de l'étude en procédant à un examen par les pairs des mérites de l'étude avant que les résultats ne soient connus. Introduit pour la première fois en 2012 (Chambers, 2013; Chambers & Tzavella, 2022), ce format de publication d'articles de journaux est devenu plus courant. Nous présentons ici une vue d'ensemble du format ainsi que huit leçons essentielles que nous avons apprises en préparant des rapports enregistrés. Nous intégrons les lignes directrices de la littérature à notre expérience pour donner un aperçu du processus de préparation et de publication d'un rapport enregistré à ceux qui ne l'ont pas encore essayé. Bien que les rapports enregistrés exigent des chercheurs qu'ils investissent davantage d'efforts aux premiers stades de la génération d'idées, de la conception et de la planification de l'analyse, ces derniers bénéficieront du retour d'information des évaluateurs au moment le plus opportun et ne craindront plus d'être rejetés en raison de limitations imprévues de l'étude ou de résultats nuls. Public Significance Statement Publication bias is the tendency for journals to publish statistically significant results, which in turn incentivizes researchers towards obtaining such results. These incentives lead to a less replicable and less robust scientific record, limiting the positive effect science can have on society. A Registered Report is a relatively new type of journal article that seeks to change the incentives: the introduction, methods, and analysis plan are proposed and peer-reviewed before the results are known. A Registered Report is then accepted based on the merits of the idea and the proposed (and then realized) plan for testing the idea. However, many scientists are not yet familiar with this format or may have trepidation in trying it. This article encourages psychological researchers to try the format by providing guidance on how to prepare a Registered Report using real examples based on experience.